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Acute leukaemia

acute leukemia
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Acute leukaemia

  1. 1. ACUTE LEUKEMIA Dr Rosline Hassan Hematology Department School of Medical Sciences USM
  2. 2. OBJECTIVE  Define acute leukemia  Classify leukemia  Understand the pathogenesis  Understand the pathophysiology  Able to list down the laboratory investigations required for diagnosis  Understand the basic management of leukemia patients
  3. 3. Acute Leukaemia  Define : heterogenous group of malignant disorders which is characterised by uncontrolled clonal and accumulation of blasts cells in the bone marrow and body tissues  Sudden onset  If left untreated is fatal within a few weeks or months  Incidence 1.8/100,000 –M’sia
  4. 4. Acute Leukemia  Classification :  Acute  Acute lymphoblastic leukemia (T-ALL & B-ALL)  Acute myeloid leukemia  Chronic  Chronic myeloid leukemia  Chronic lymphocytic leukemia
  5. 5. FAB Acute Myeloid Leukemia Acute nonlymphocytic (ANLL) % Adult cases M0 Minimally differentiated AML 5% - 10% Negative or < 3% blasts stain for MPO ,PAS and NSE blasts are negative for B and T lymphoid antigens, platelet glycoproteins and erythroid glycophorin A. Myeloid antigens : CD13, CD33 and CD11b are positive. M1 Myeloblastic without maturation 10 - 20% >90% cells are myeloblasts 3% of blasts stain for MPO +8 frequently seen
  6. 6. M2 AML with maturation 30 - 40% 30% - 90% are myeloblasts ~ 15% with t(8:21)
  7. 7. M3 Acute Promyelocytic Leukemia (APML) 10-15% marrow cells hypergranul promeyelocytes Auer rods/ faggot cells may be seen Classical-Hypergranular, 80% leukopaenic Variant-Hypogranular, leukocytosis Granules contain procoagulants (thromboplastin-like) - massive DIC t(15:17) is diagnostic
  8. 8. M4 Acute Myelomonocytic Leukemia 10-15% Incresed incidence CNS involvement Monocytes and promonocytes 20% - 80% M4 with eosinophilia ((M4-Eo), assoc with del/inv 16q – marrow eosinophil from 6% - 35%,
  9. 9. M5a Acute Monoblastic Leukemia 10-15% M5b AMoL with differentiation <5% Often asso with infiltration into gums/skin Weakness, bleeding and diffuse erythematous skin rash
  10. 10. M6 Erythroleukemia (Di Guglielmo) <5% 50% or more of all nucleated marrow cells are erythroid precursors, and 30% or more of the remaining nonerythroid cells are myeloblasts (if <30% then myelodysplasia)
  11. 11. M7 Acute Megakaryoblastic Leukemia <5% Assoc with fibrosis (confirm origin with platelet peroxidase + electron microscopy or MAb to vWF or glycoproteins
  12. 12. FAB Acute Lymphoblastic Leukemia Acute lymphoblastic leukemia (ALL)* L-1 85% L-2 14% L-3 (Burkitt's)1% childhood
  13. 13. Acute Leukaemogenesis Develop as a result of a genetic alteration within single cell in the bone marrow a) Epidemiological evidence : 1. Hereditary Factors · Fanconi’s anaemia · Down’s syndrome · Ataxia telangiectasia
  14. 14. Acute Leukaemogenesis 2. Radiation, Chemicals and Drugs 3. Virus related Leukemias  Retrovirus :- HTLV 1 & EBV
  15. 15. Acute Leukaemogenesis b)Molecular Evidence  Oncogenes :  Gene that code for proteins involved in cell proliferation or differentiation  Tumour Suppressor Genes :  Changes within oncogene or suppressor genes are necessary to cause malignant transformation.
  16. 16. Acute Leukaemogenesis Oncogene can be activated by : · chromosomal translocation · point mutations · inactivation  In general, several genes have to be altered to effect neoplastic transformation
  17. 17. Pathophysiology  Acute leukemia cause morbidity and mortality through :-  Deficiency in blood cell number and function  Invasion of vital organs  Systemic disturbances by metabolic imbalance
  18. 18. Pathophysiology A. Deficiency in blood cell number or function i. Infection - Most common cause of death - Due to impairment of phagocytic function and neutropenia
  19. 19. Pathophysiology ii. Hemorrhage - Due to thrombocytopenia or 2o DIVC or liver disease iii. Anaemia - normochromic-normocytic - severity of anaemia reflects severity of disease - Due to ineffective erythropoiesis
  20. 20. Pathophysiology B. Invasion of vital organs - vary according to subtype i.Hyperleukocytosis - cause increase in blood viscosity - Predispose to microthrombi or acute bleeding - Organ invole : brain, lung, eyes - Injudicious used of packed cell transfusion precipitate hyperviscosity
  21. 21. Pathophysiology ii. Leucostatic tumour - Rare - blast cell lodge in vascular system forming macroscopic pseudotumour – erode vessel wall cause bleeding iii. Hidden site relapse - testes and meninges
  22. 22. Pathophysiology C. Metabolic imbalance - Due to disease or treatment - Hyponatremia vasopressin-like subst. by myeloblast - Hypokalemia due to lysozyme release by myeloblast - Hyperuricaemia- spont lysis of leukemic blast release purines into plasma
  23. 23. Acute Lymphoblastic Leukaemia  Cancer of the blood affecting the white blood cell known as LYMPHOCYTES.  Commonest in the age 2-10 years  Peak at 3-4 years.  Incidence decreases with age, and a secondary rise after 40 years.  In children - most common malignant disease  85% of childhood leukaemia
  24. 24. Acute Lymphoblastic Leukemia Specific manifestation : *bone pain, arthritis *lymphadenopathy *hepatosplenomegaly *mediastinal mass *testicular swelling *meningeal syndrome
  25. 25. Acute Myeloid Leukemia  Arise from the malignant transformation of a myeloid precursor  Rare in childhood (10%-15%)  The incidence increases with age  80% in adults  Most frequent leukemia in neonate
  26. 26. Acute Myeloid Leukemia Specific manifestation : - Gum hypertrophy  Hepatosplenomegaly  Skins deposit  Lymphadenopathy  Renal damage  DIVC
  27. 27. Investigations 1. Full blood count  reduced haemoglobin normochromic, normocytic anaemia,  WBC <1.0x109/l to >200x109/l, neutropenia and f blast cells  Thrombocytopenia  <10x109/l).
  28. 28. Investigations Acute lymphoblastic leukemia Acute myeloid leukemia
  29. 29. Investigations  ALL(Lymphoblast )  Blast size :small  Cytoplasm: Scant  Chromatin: Dense  Nucleoli :Indistinct  Auer-rods: Never present  AML (Myeloblast)  Large  Moderate  Fine, Lacy  Prominent  Present in 50%
  30. 30. Investigations 2. Bone marrow aspiration and trephine biopsy · confirm acute leukaemia (blast > 30%)  usually hypercellular
  31. 31. Investigations 3. Cytochemical staining a) Peroxidase :-  * negative ALL  * positive AML Positive for myeloblast
  32. 32. Investigations b) Periodic acid schiff *Positive ALL (block) * Negative AML Block positive in ALL
  33. 33. Investigations c) Acid phosphatase : focal positive (T-ALL)
  34. 34. Investigations 4.Immunophenotyping · identify antigens present on the blast cells · determine whether the leukaemia is lymphoid or myeloid(especially important when cytochemical markers are negative or equivocal. E.g : AML-MO) · differentiate T-ALL and B-ALL
  35. 35.  Certain antigens have prognostic significance  Rare cases of biphenotypic where both myeloid and lymphoid antigen are expressed  Able to identify the subtype of leukemia. E.g : AML-M7 has a specific surface marker of CD 61 etc
  36. 36.  Monoclonal antibodies(McAb) are recognised under a cluster of differentiation(CD). MONOCLONAL ANTIBODIES USED FOR CHARACTERISATION OF ALL AND AML. Monoclonal antibodies AML : CD13, CD33 ALL : B-ALL CD10, CD 19, CD22 T-ALL CD3, CD7
  37. 37. Investigations 5. Cytogenetics and molecular studies  detect abnormalities within the leukaemic clone  diagnostic or prognostic value  E.g : the Philadelphia chromosome : the product of a translocation between chromosomes 9 and 22  confers a very poor prognosis in ALL
  38. 38. Investigations COMMON CHROMOSOME ABNORMALITIES ASSOCIATED WITH ACUTE LEUKEMIA  t(8;21) AML with maturation (M2)  t(15;17) AML-M3(APML)  Inv 16 AML-M4  t(9;22) Chronic granulocytic leukemia  t(8;14) B-ALL
  39. 39. Others Invx 6. Biochemical screening  leucocyte count very high - renal impairment and hyperuricaemia 7. Chest radiography · mediastinal mass - present in up to 70% of patients with T -ALL In childhood ALL bone lesions may also seen.
  40. 40. Others Invx 8.Lumbar puncture  initial staging inv. to detect leukaemic cells in the cerebrospinal fluid, indicating involvement of the CNS  Done in acute lymphoblastic leukemia
  41. 41. Management Supportive care 1. Central venous catheter inserted to :  facilitate blood product  adm. of chemotherapy and antibiotics  frequent blood sampling
  42. 42. Management 2. Blood support :-  platelet con. for bleeding episodes or if the platelet count is <10x109/l with fever  fresh frozen plasma if the coagulation screen results are abnormal  packed red cell for severe anaemia (caution : if white cell count is extremely high)
  43. 43. Management 3. Prevention and control infection  barrier nursed  Intravenous antimicrobial agents if there is a fever or sign of infection
  44. 44. Management 4.Physiologic al and social support
  45. 45. Specific treatment Used of cytotoxic chemotherapy.  Aim : · To induce remission  (absence of any clinical or conventional laboratory evidence of the disease)  To eliminate the hidden leukemic cells
  46. 46. Cytotoxic chemotherapy  Anti-metabolites  Methotrexate  Cytosine arabinoside  Act: inhibit purine & pyrimidine synt or incorp into DNA  S/E : mouth ulcer, cerebellar toxicity  DNA binding  Dounorubicin  Act : bind DNA and interfere with mitosis  S/E : Cardiac toxicity, hair loss
  47. 47. Cytotoxic chemotherapy  Mitotic inhibitors  Vincristine  Vinblastine  Act : Spindle damage, interfere with mitosis  S/E : Neuropathy, Hair loss  Others  Corticosteroid  Act : inhibition or enhance gene expression  Trans-retinoic acid  Act : induces differentiation
  48. 48. Complications Early side effects  nausea and vomiting  mucositis, hair loss, neuropathy, and renal and hepatic dysfunction  myelosuppression
  49. 49. Complications Late effects  Cardiac –Arrhythmias, cardiomyopathy  Pulmonary –Fibrosis  Endocrine –Growth delay, hypothyroidism, gonadal dysfunction  Renal –Reduced GFR  Psychological –Intellectual dysfunction,  Second malignancy  Cataracts
  50. 50. Poor Prognostic Factors ALL AML Age <1 > 60 year TWBC > 50 x 109/l High CNS present present (rare) Sex male male/female Cytogenetic t(9;22) monosomy 5, 7

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